1. Field of the Invention
This invention generally relates to chemicals that bind to receptors in the TRP (transient receptor potential) ion channel family, more particularly to the subgroup of long TRP (or TRPM) channels, and most particularly to those that specifically bind to the TRP channel called TRP-M8 (trp-p8, CMR1); TRP-M8 receptors are present in sensory nerves and activation of these receptors results in cold sensations. These receptors are also at elevated levels in certain cancers, such as prostate and breast cancer. This invention more particularly relates to TRP binding compositions containing radioactive fluorine and iodine 18F, 123I, 125I, or 131I, within the molecular structure, said compositions being useful, for example, in radioreceptor, diagnostic imaging, and radiotherapeutic applications.
2. Description of Related Art
About two decades ago a group of scientists discovered novel compounds that have a physiological cooling action on the skin. These were described in U.S. Pat. No. 4,193,936 (Watson et al., Mar. 18, 1980), U.S. Pat. No. 4,248,859 (Rowsell et al, Feb. 3, 1981) and U.S. Pat. No. 4,318,900 (Rowsell, Mar. 9, 1982). Much more recently a new physiological receptor was discovered. This 1104-amino acid protein, deciphered from the cDNA sequence, was named trp-p8 because of its structural homology to receptors of the transient receptor potential (TRP) family. The mRNA for the synthesis of this specific protein was also detected in samples of malignant prostate, mammary gland cells, melanoma, and colorectal cancer cells. The functional role, if any, of TRP-M8 receptors on malignant cells is not known.
The TRP-M8 sequence of the gene/protein was published in Cancer Research (vol. 61, pg. 3760–3769, May 1, 2001. L. Tsavaler, M. H. Shapero, S. Morkowski, and R. Laus: “Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins”). Soon afterwards it was discovered that this receptor was present in sensory neurons and transduced the sensations of cold temperatures (McKemy et al. “Identification of a cold receptor reveals a general role for TRP channels in thermosensation”. Nature 416: 52–58, March 2002). Chemicals that elicit sensations of cold, such as menthol and icilin, bind to and activate the cold receptor, as measured by binding constants and by calcium influxes into the cells.
A nomenclature panel composed of experts in the field has recommended the TRP-M8 designation for the cold/prostate receptor because of its structural homology to other protein receptors in this family. However, some still call this receptor trp-p8 or CMR1 (cold-menthol receptor). The tags for the TRP-M8 sequences in the NicePro TrEMBL Database are Q8R405 (mouse TRP-M8), Q8R444 (rat TRP-M8 or CMR1) and Q8TAC3 (human TRP-M8, or trp-p8). The corresponding identity tags in the GenBank are AF4811480 and AY095352 (mouse), AY072788 (rat) and AY090109 (humans).
Various radioactive fluorine and iodine compounds are used in clinical oncology. For example, 18F and 123I are used in positron emission tomography (PET) and single-photon emission computed tomography (SPECT), respectively, for the imaging, diagnosis and staging of neoplastic disease. 125I and 131I are used for the treatment of cancer, especially thyroid cancer. Radioiodine compounds in thyroid therapy are remarkably effective because iodine is incorporated specifically into the thyroid hormones (thyroxin and tri-iodothyronine). Hence, the malignant cells are selectively and specifically targeted, with minimal damage to normal cells and adverse side effects.
Prostate cancer is the most common cancer among men in the United States. There is no universally agreed-upon strategic plan for its diagnosis and management. Brachytherapy, a treatment well known in the art, involves the implantation of radioactive seeds directly into the prostate gland. The radioactive seeds used in brachytherapy may include iodine-125, iodine-131, palladium, radium, iridium, or cesium.
The pharmacological strategy, to bring radio-labeled compounds to specific targets in malignant cells, to improve diagnosis, or to treat certain cancers, is called targeted radiodiagnostics and targeted radiotherapy. New radiofluorinated and radioiodinated compounds useful for these applications are being sought.